Anatomic Pathology Selected Abstracts, 6/13

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Survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer

Since 1999, patients with low-risk endometrial cancer, as defined by criteria set by the Mayo Clinic, have preferably not undergone lymphadenectomy (LND) at the Mayo Clinic. The authors prospectively assessed survival, sites of recurrence, morbidity, and cost in this low-risk cohort. Cause-specific survival was estimated using the Kaplan-Meier method and compared using the log-rank test. Complications were graded per the Accordion Severity Grading System. Thirty-day cost analyses were expressed in 2010 Medicare dollars. The authors found that among 1,393 consecutive surgically managed cases, 385 (27.6 percent) met inclusion criteria, accounting for 34.1 percent of type I endometrial cancer. There were 80 lymphadenectomy (LND) and 305 non-LND cases. Complications in the first 30 days were significantly more common in the LND cohort (37.5 percent versus 19.3 percent; P<.001). The prevalence of lymph node metastasis was 0.3 percent (one in 385). Over a median followup of 5.4 years, only five of 31 deaths were due to disease. The five-year cause-specific survival in LND and non-LND cases was 97.3 percent and 99 percent, respectively (P=.32). None of the 11 total recurrences occurred in the pelvic or para-aortic nodal areas. Median 30-day cost of care was $15,678 for LND cases and $11,028 for non-LND cases (P<.001). The estimated cost per upstaged low-risk case was $327,866 to $439,990, adding an additional $1,418,189 if all 305 non-LND cases had undergone LND. The authors concluded that lymphadenectomy dramatically increases morbidity and cost of care without discernible benefits in low-risk endometrial cancer, as defined by the Mayo criteria. In these low-risk patients, hysterectomy with salpingo-oophorectomy alone is appropriate surgical management and should be the standard of care.

Dowdy SC, Borah BJ, Bakkum-Gamez JN, et al. Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer. Gyn Oncol. 2012;127:5–10.

Correspondence: Dr. Sean C. Dowdy at dowdy.sean@mayo.edu

Role of Ki-67 proliferative index in predicting survival for patients with pulmonary carcinoid tumors

Pulmonary carcinoid tumors are classified as typical or atypical based on the mitotic index (two per 10 high-power fields) or the presence of necrosis, or both. Following incorporation of the Ki-67 index into the classification of gastrointestinal carcinoid tumors, the oncologists at the authors’ institution have been requesting this test as part of the workup of pulmonary carcinoid tumors, although no established criteria exist for interpreting Ki-67 index in these neoplasms. The authors used the Ariol SL50 image analyzer to measure the Ki-67 index in 101 pulmonary carcinoid tumors (78 typical and 23 atypical) and then correlated the Ki-67 index and the histological diagnoses in univariate and multivariable analyses with overall survival. The mean Ki-67 indices for the typical carcinoids (3.7 standard deviation ± 4.0) and the atypical carcinoids (18.8 standard deviation ± 17.1) were significantly different (P<.001), although the frequency distributions of Ki-67 indices in the two groups overlapped considerably. Receiver operating characteristic curve analysis showed that a Ki-67 index cutoff value of five percent provided the best fit for specificity and sensitivity in predicting overall survival. Histological diagnosis and the Ki-67 index cutoff of five percent were each independently strong predictors of survival (P<.001 and P=.003, respectively). When considered together in multivariable analysis, histological diagnosis was the stronger predictor of overall survival, and a Ki-67 index cutoff of five percent did not provide additional significant predictive survival information within the typical or atypical carcinoid patient groups. A few typical carcinoid patients with Ki-67 indices of five percent appeared to have worse survival after five years than those with Ki-67 indices of less than five percent, but the data set was insufficiently powered to further analyze this finding. These findings do not provide best evidence for routine use of the Ki-67 index to prognosticate overall short-term survival in patients with pulmonary carcinoid tumors.

Walts AE, Ines D, Marchevsky AM. Limited role of Ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumors. Mod Pathol. 2012;25:1258–1264.

Correspondence: Dr. A. E. Walts at walts@cshs.org

Grading neuroendocrine tumors using Ki-67 proliferation index

Gastrointestinal and pancreatic neuroendocrine tumors arise from disseminated neuroendocrine cells, expressing general and specific neuroendocrine markers. The World Health Organization 2010 classification of neuroendocrine tumors (NETs) is based on grading them according to the proliferation index, which is determined by immunohistochemical staining of the nuclear antigen Ki-67. The classification introduces Ki-67 as the most important criterion for tumor grading, influencing patients’ prognoses and choice of treatment. The authors conducted a study to assess proliferation index value in NETs and its influence on tumor grading. The tumor material consisted of 51 NETs from the pancreas (n=31) and ileum (n=20). The slides were stained with the Ki-67 antibody and visualized using a polymer kit. Proliferation index was assessed visually by microscope oculars and using the public-domain, image-analysis software ImmunoRatio. The proliferation index was measured from the most proliferative areas of the tumor. The index values and tumor grade by ImmunoRatio were highly reproducible as compared with conventional assessment, which suffered from variation, especially if ascertained by different observers. Computer-aided assessments had almost perfect correlation (r=0.985, r=0.987, and r=0.995; P=.000) and reproducibility (k=0.886, k=0.886, and k=1.000; P=.000) in proliferation index values and tumor grades, respectively. The authors concluded that the proliferation index values and tumor grade between conventional and ImmunoRatio assessments by a qualified observer were in good agreement. ImmunoRatio is a qualified diagnostic aid to more objectively analyze Ki-67 proliferation index-based tumor grade in NETs.

Remes SM, Tuominen VJ, Helin H, et al. Grading of neuroendocrine tumors with Ki-67 requires high-quality assessment practices. Am J Surg Pathol. 2013;36(9):1359–1363.

Correspondence: Satu Maria Remes at satu.remes@hus.fi

Dermal hypersensitivity reaction: a PCR-confirmed pattern of herpetic dermatitis

Herpetic dermatitis, whether due to herpes simplex virus (HSV) or varicella zoster virus, can present with similar clinical and histopathologic features. Further confounding matters, viral cytopathic changes are not always observed in biopsy specimens. Therefore, use of polymerase chain reaction (PCR) analysis can play an integral role in the definitive diagnosis of herpetic dermatitis and in distinguishing HSV I/HSV II from varicella zoster virus (VZV). The authors performed a study in which 40 patients with skin biopsies from 2004 to 2011 had PCR analysis performed to detect HSV I/II or VZV. Patient demographics, clinical impression, and histopathologic characteristics were reviewed and correlated with PCR findings. The authors found that, overall, complete correlation between clinical impression, histopathology, and PCR results was noted in 21 of 40 cases. In 19 cases, clinical impression and histopathology were discrepant, and in 15 of these cases PCR confirmed HSV or VZV infection. The authors also described three cases of herpetic dermatitis without viral change that histopathologically demonstrate the pattern of a dermal hypersensitivity reaction. The results of this study suggest that routine use of PCR for the definitive diagnosis of herpetic dermatitis should be considered when there is a clinical suspicion of herpes virus infection, even when specific histopathologic findings are lacking. Additionally, a dermal hypersensitivity reaction should be recognized as one histopathologic manifestation of herpes incognito.

Kinonen CL, Gleason BC, Thomas AB, et al. Dermal hypersensitivity reaction: a PCR-confirmed pattern of herpetic dermatitis. J Cutan Pathol. 2012;39(10):929–935.

Correspondence: Dr. Thomas Cibull at tcibull@northshore.org

Ramifications of urologists’ self-referral for pathology of biopsy specimens

Federal law allows physicians, in some circumstances, to refer patients for additional services to a facility in which the physician has a financial interest. The practice of physician self-referral for imaging and pathology services has been criticized because it can lead to increased use and escalating health care expenditures, with little or no benefit to patients. The author conducted a study in which she examined Medicare claims for men in a set of geographically dispersed counties to determine how the “in-office ancillary services” exception affected the use of surgical pathology services and cancer-detection rates associated with prostate biopsies. The author found that self-referring urologists billed Medicare for 4.3 more specimens per prostate biopsy than the adjusted mean of six specimens per biopsy that non-self-referring urologists sent to independent pathology providers, a difference of almost 72 percent. Additionally, the regression-adjusted cancer detection rate in 2007 was 12 percentage points higher for men treated by urologists who did not self-refer. This suggests that financial incentives prompt self-referring urologists to perform prostate biopsies on men who are unlikely to have prostate cancer. These results support closing the loophole that permits self-referral to in-office pathology laboratories.

Mitchell JM. Urologists’ self-referral for pathology of biopsy specimens linked to increased use and lower prostate cancer detection. Health Affairs. 2012;31(4):741–749.

Correspondence: Dr. Jean Mitchell at mitchejm@georgetown.edun